Locomotor and Reinforcing Effects of Pentedrone, Pentylone and Methylone in Rats

Abstract

The broad diversity of synthetic cathinone psychostimulant drugs that are available to users complicates research efforts to provide understanding of health risks. Second generation cathinones pentedrone and pentylone are distinguished from each other by the 3,4-methylenedioxy structural motif (which distinguishes methamphetamine from 3,4-methylenedioxymethamphetamine) and each incorporates the α-alkyl chain motif contained in the transporter-inhibitor cathinones (3,4-methylenedioxypyrovalerone (MDPV), α-pyrrolidinopentiophenone (α-PVP)) but not in the monoamine releasers (mephedrone, methylone). Studies were conducted in male and female Wistar rats to compare locomotor and thermoregulatory effects of pentedrone, pentylone and methylone using an implanted radiotelemetry system. Reinforcing effects were assessed in female Wistar rats trained in the intravenous self-administration (IVSA) procedure and subjected to dose-substitution (0.025-0.3 m/gkg/inf) under a fixed-ratio 1 response contingency. Pentedrone, pentylone and methylone dose-effect curves were contrasted with those for α-PVP and α-pyrrolidinohexiophenone (α-PHP). Dose dependent increases in locomotion were observed after intraperitoneal injection of pentylone (0.5-10.0 mg/kg), pentedrone (0.5-10.0 mg/kg) or mephedrone (0.5-10.0 mg/kg) in male and female rats. The maximum locomotor effect was similar across drugs but lasted longest after pentedrone. Mean body temperature did not vary systematically more than 0.5 °C after pentedrone or pentylone in either sex. A sustained hyperthermia (0.4-0.8 °C) was observed for four hours after 10 mg/kg methylone in male rats. More infusions of pentedrone or pentylone were self-administered compared with methylone, but all three were less potent than α-PVP or α-PHP. These studies support the inference that second generation cathinones pentylone and pentedrone have abuse liability greater than that of methylone.peer-reviewed)

Stereoselective neurochemical, behavioral, and cardiovascular effects of α‐pyrrolidinovalerophenone enantiomers in male rats

“…The effects of α-PVP on temperature were small and failed to reach significance, although racemic α-PVP tended to increase body temperature. Our results agree with the findings of Nelson et al, 26 Finally, confirming what others have shown for racemic α-PVP, 20,24,[28][29][30][31][32][33] rats self-administered α-PVP at doses similar to racemic MDPV. 45 Self-administration was acquired rapidly with α-PVP, and the drug produced a typical inverted U-shaped dose-effect function comparable with other psychomotor stimulants.…”

“…Finally, confirming what others have shown for racemic α‐PVP, 20,24–24,28–33 rats self‐administered α‐PVP at doses similar to racemic MDPV 45 . Self‐administration was acquired rapidly with α‐PVP, and the drug produced a typical inverted U‐shaped dose‐effect function comparable with other psychomotor stimulants.…”

“…It produces place preference in mice and rats, 21,22,26 and it reduces intracranial self-stimulation thresholds 27 and is self-administered by rats. 20,24,[28][29][30][31][32][33] α-PVP also generalizes to other psychomotor stimulants in drug discrimination procedures carried out in rodents and monkeys. 22,34,35 MDPV has two enantiomers, R and S, based on absolute configuration.…”

Methylenedioxymethamphetamine-like discriminative stimulus effects of pyrrolidinyl cathinones in rats

“…These compounds largely act as inhibitors of monoamine transporters and, in general, are selective for the dopamine transporter (DAT) over the norepinephrine (NET) or serotonin (SERT) transporters (e.g., Eshleman et al 2017;Gannon et al, 2018a;Meltzer et al, 2006). Several of the compounds are self-administered, including αpyrrolidinopropiophenone (α-PPP; Aarde et al, 2015;Gannon et al, 2018b), 4′-methyl-α-pyrrolidinopropiophenone (4′-MePPP; Huskinson et al, 2017), α-pyrrolidinovalerophenone (α-PVP; Huskinson et al, 2017;Javadi-Paydar et al, 2018), 3,4-methylenedioxy-pyrovalerone (MDPV; Aarde et al, 2013;Gannon et al, 2017Gannon et al, , 2019Watterson et al, 2014), α-pyrrolidinopentiothiophenone (α-PVT; Cheong et al, 2017), and α-pyrrolidinohexiophenone (α-PHP; Javadi-Paydar et al, 2018). MDPV (Atehortua-Martinez et al, 2019;Karlsson et al, 2014;King et al, 2015) and α-PVT (Cheong et al, 2017) produced a conditioned place preference, and MDPV increased intracranial self-stimulation (ICSS; Bonano et al, 2014;Geste et al, 2018;Watterson et al, 2014).…”

HIV-1 and microglia: EcoHIV and HIV-1 transgenic rats

“…Furthermore, brain regions exhibiting high HIV-1 mRNA expression also correspond with neuroanatomical alterations previously observed in the HIV-1 Tg rat. Broadly, the HIV-1 Tg rat exhibits synaptic dysfunction 32,35,44 , neurotransmitter system alterations 68,36 , and neuroinflammation 39 ; deficits which have been implicated in the pathogenesis of HAND. More specifically, profound synaptic dysfunction has been observed in both pyramidal neurons from layers II-III of the mPFC 32 and medium spiny neurons from the NAc 35,44 evidenced by alterations in dendritic branching complexity and synaptic connectivity in HIV-1 Tg animals relative to controls.…”